Cholesterol, Lipoprotein Metabolism And Steroids Flashcards

1
Q

Organic compound with four fused rings arranged in a specific configuration (ABCD ring system)

A

Steroids

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2
Q

A subgroup of steroids with a hydroxyl group at the 3-position of the A-ring

A

Sterol

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3
Q

Cholesterol structure

A

HO-A ring-B ring-C ring-D ring-hydrocarbon tail

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4
Q

Is cholesterol hydrophilic or hydrophobic?

A

Hydrophobic

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5
Q

What is the major sterol in animal tissues?

A

Cholesterol

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6
Q

Cholesterol is a precursor for the synthesis of what 3 compounds?

A

Bile salts

Steroid hormones

Vitamin D

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7
Q

Cholesterol function

A

Essential structural component of animal cell membranes (30%)

required to maintain both membrane structural integrity and fluidity at different temperatures

Enables animal cells to dispense within cell shape in order to protect membrane integrity and cell viability

Components of lipid rafts formation to facilitate cell signaling

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8
Q

Where is free cholesterol found?

A

Membranes of animal cell membranes

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9
Q

Free cholesterol is..

A

Unesterified. Hydroxyl group on A-ring

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10
Q

Esterified cholesterol is…

A

Esterified, or cholesteryl ester. A-ring has a fatty acid attached to the Oxygen

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11
Q

Are esterified cholesterol in the membranes?

A

Nope

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12
Q

Where are esterified cholesterol found?

A

Plasma. Most plasma cholesterol is in this form.

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13
Q

What cells a can synthesize cholesterol?

A

Most, but significantly from Liver, Intestine, and steroidogenic tissues.

Steroidogenic=adrenal cortex, testes, ovaries

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14
Q

What organs controls the overall cholesterol homeostasis?

A

Liver (synthesis, distribution, and elimination)

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15
Q

Sources of liver cholesterol

A

De novo synthesis

Diet

HDLs

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16
Q

Routes for cholesterol clearance from the liver

A

Secretion into VLDL/LDL

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17
Q

What leads to gradual deposition of cholesterol in the tissues?

A

The balance between cholesterol influx and efflux isn’t precise

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18
Q

Where does the cholesterol typically deposit?

A

Endothelial linings of blood vessels

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19
Q

Lipid depositions over time leads to

A

Plaque formation

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20
Q

Plaque formation, from lipid deposition, causes what?

A

Atherosclerosis. The narrowing of blood vessels

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21
Q

Atherosclerosis is important because

A

It causes an increased risk of cardio, cerebro, and peripheral vascular disease

May be life-threatening.

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22
Q

Substrates for Cholesterol Synthesis

A

Acetyl CoA
NADPH
ATP

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23
Q

cholesterol synthesis will occur under what conditions?

A

In well-fed state (when the substrates are available)

When the cholesterol supply is low

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24
Q

Synthesis of Cholesterol occurs in the…

A

Hepatocytes

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25
Q

Synthesis of Cholesterol in Hepatocytes

A
  1. Conversion of Acetyl CoA to HMG CoA
    - via HMG CoA synthase
  2. Synthesis of mevalonate
    - via HMG-CoA reductase
    - RATE LIMITING
    - inhibited by station drugs
  3. Conversion of mevalonate to isoprenyl pyrophosphates the loss of CO2
  4. Conversion of isoprenylpyrophosphosphates to squalene
  5. Conversion to squalene to lanosterol
  6. Conversion of Lanosterol to cholesterol
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26
Q

What is the rate limiting step of Synthesis of Cholesterol?

A

Synthesis of Mevalonate

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27
Q

What is cholesterol synthesis inhibited by?

A

Statin drugs

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28
Q

How many molecules of Mevalonate and Acetyl CoA are required for Cholesterol Synthesis?

For 1 cholesterol molecule

A

6 molecules of Mevalonate

18 molecules of Acetyl CoA

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29
Q

What enzyme regulates Cholesterol Synthesis?

A

HMG CoA Reductase.

Of stage 2, synthesis of Mevalonate

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30
Q

What part of the cell does cholesterol synthesis occur?

A

Cytoplasm. Intermediates must be charged to make them soluble. Associated with carrier proteins.

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31
Q

Regulation of Cholesterol Synthesis via HMG CoA Reductase

A

Sterol dependent regulation of the levels of the enzyme protein product

Sterol independent covalent modifications - phosphorylation/dephosphorylation

Hormonal regulation

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32
Q

Can the ring structure of cholesterol be metabolized to CO2 and H2O?

A

Nope

33
Q

The intact sterol nucleus of cholesterol is eliminated by:

A

Conversion to bile acids and bile salts (excreted into feces)

Secretion of cholesterol into the bile (Into feces)

Modified by bacteria (before excretion into intestine)

34
Q

Watery mixture of organic and inorganic compounds produced by the liver to facilitate the digestion of lipids in the small intestine

A

Bile

35
Q

Major constituent of bile produced in liver cells from bile acids

A

Bile salts

36
Q

Precursor for the synthesis of bile salts, produced in liver cells from cholesterol

A

Bile acids

37
Q

Synthesis of bile salts

A

Cholesterol -> Bile Acids -> Bile salts

38
Q

Where are bile salts reabsorbed?

A

In the small intestine, 95% of bile salts are reabsorbed here

Sent back to the liver to be used again

39
Q

What happens to the amount of bile salts that aren’t reabsorbed?

A

They are lost in the feces, only significant loss of the steroid nucleus.

Around 5%

40
Q

Formation of gall stones in the gall bladder, where bile is stored

A

Cholelithiasis

41
Q

How are gall stones formed?

A

Too much cholesterol and/or too little bile salts

Bile salts solubize free cholesterol

42
Q

Causes of Cholelithiasis

A

Inefficient enterohepatic cycling of bile salts (AKA not reabsorbed)

Liver dysfunction

Other idiopathic reasons????

43
Q

Spherical macromolecular complexes of lipids and specific proteins

A

Lipoproteins

44
Q

What are the specific proteins associated with lipoproteins called?

A

Apolipoproteins

45
Q

What is the function of lipoproteins?

A

To transport cholesterol, fats, and fat soluble compound in the plasma

46
Q

What are the 4 types of lipoproteins?

A

Chylomicrons, VLDLs, LDLs, HDLs

47
Q

Which lipoprotein is responsible for transport of dietary lipids, and is produced in enterocytes?

A

Chylomicrons

48
Q

What lipoprotein is responsible for the transport of newly synthesized lipids produced in Hepatocytes?

A

VLDLs, very low density lipoproteins

49
Q

What lipoproteins is responsible for the transport of cholesterol to peripheral tissues?

A

LDLs, low density lipoproteins

50
Q

What lipoprotein is responsible for the transport of cholesterol from the periphery to the liver?

A

High Density Lipoproteins, HDLs

51
Q

Lipoprotein composition (cores, surface, proteins associated with them)

A

Core: neutral lipid, TAG and cholesterol esters, hydrophobic

Polar lipid surface: composed of phospholipid (PC and CM) and free cholesterol, hydrophilic

Amphipathic lipoproteins: 11 different types of Apo proteins found in humans, specific for each class (ApoA, ApoB, ApoC, ApoD, Apo(a))

52
Q

Which lipoproteins is largest in size, least dense, and contains the highest percentage of fat?

A

Chylomicrons

53
Q

Which lipoproteins are smaller and more dense (than Chylomicrons)?

A

VLDLs

54
Q

Which lipoproteins carry the “bad” cholesterol?

A

LDLs

55
Q

Which lipoproteins contain the second highest percentage of cholesterol, and carry the “good” cholesterol?

A

HDLs

56
Q

Chylomicrons

A

Sizes vary, depending on the meal content

Largest lipoproteins in size

Least dense

Contain highest percentage of fat

Produced by gut cells.

Contain mainly TAGs.

57
Q

VLDLs

A

Very similar to chylomicrons

Produced by Hepatocytes

Smaller and more dense than Chylomicrons

Contain high percentage of fat

Distributes fat to peripheral tissues (away from the liver)

Contain mainly TAGs, but less than Chylomicrons

58
Q

LDLs

A

Highest percentage of cholesterol

Distribute cholesterol to peripheral tissues

Produced from VLDL via lipolysis in blood

Carry the “bad” cholesterol

59
Q

HDLs

A

Contain the highest percentage of protein

Reservoir of lipoproteins

Contain second highest percentage of cholesterol

Carry the “good” cholesterol

Smallest of the lipoproteins

60
Q

How are lipoproteins measured?

A

In plasma lipid profiling, blood is taken and analyses their blood in fasting state. Usually takes 10-12 hours overnight.

61
Q

Metabolism of Chylomicrons

A
  1. Chylomicrons are formed in the ER, and Golgi of intestinal mucosal smells, using Apo-48 as scaffold protein
  2. Lipids are transferred to ApoB-48 via a MTP (Microsomal Transfer Protein)
  3. “Nascent” Chylomicrons are excreted through the plasma membrane into the lymph
  4. From the lymph they enter the blood
  5. Peripheral cells then hydrolase TAGs to FA and glycerol
  6. Remaining is cleared from the blood stream by the liver (via Endocytosis)
62
Q

Metabolism of VLDLs

A
  1. VLDLs are assembled in the ER and Golgi of liver cells
  2. Directl secreted into blood
  3. LPL hydrolyzes VLDLs’ TAGs and real eases FA to peripheral tissues
  4. VLDL decrease in size and become denser…LDL
  5. Transfer of cholesterol esters from HDL further make the VLDL into an LDL
  6. Apo B-100 remaining in LDL is a ligand recognized by the LDL receptors. (Breaks down lipids and recycles monomers)
63
Q

Possible fates of LDL-delivered cholesterol (bad cholesterol)

A
  1. It can be immediately used for steroid or bile acid synthesis
  2. If not immediately used, it can be converted to CE by ACAT and stored in lipid droplets
    - oversupply of cholesterol functions as major regulator of the overall cholesterol homeostasis
64
Q

What happens if there is an oversupply of cholesterol?

A

Inhibit de novo synthesis of cholesterol

Inhibit expression of LDLR, resulting in decreased LDL uptake

Activate ACAT to produce more CE

65
Q

LDL is directly related to

A

Atherosclerosis

66
Q

Factors increasing propensity for producing modified LDLs in circulation

A
  • high BP
  • Oxidative stress caused by infection, smoking, certain drugs
  • Chemicals present in tobacco smoke
67
Q

Smokers and diabetics will have an increased risk in:

A

Cardiovascular disease, due to modified LDLs

68
Q

What does it mean by “good” cholesterol?

A

Elevated HDLs, in comparison to LDLs. A ratio

69
Q

The efflux of cholesterol from peripheral tissues to HDL

A

Reverse Cholesterol Transport

70
Q

HDLs are a reservoir of _______, and therefore reflect its association with __________

A

Proteins, Apolipoproteins

71
Q

Metabolism of HDL

A

HDLs are not well understood.

  1. HDLs Apo A1 is produced in liver and intestinal cells and secreted in circulation
  2. Free Apo A1 interacts with ABCA1 transporter that transfer phospholipids and cholesterol from peripheral cells to lipid poor Apo A1
  3. Lipid acted ApoA1 is gradually converted to discoidal particles enriched in free cholesterol, which become spherical
  4. HDLs also serve as a resolver of ApoCII and ApoE for transfer of otherlipoproteins
  5. HDL isn’t taken up by the liver, but transfers cholesteryl esters from HDL to liver via CETP
72
Q

Lipoprotein Metabolism Related Diseases

A

Type 1 Hyperlipoproteinemia
-deficiency of Apo CII or LPL

Type IIa Hyperlipidema
-defect in LDL

Type III Hyperlipoproteinemia
-defective Apo E protein synthesis

Abetalipoproteinemia

  • defect in Microsomal Transfer protein (MTP)
  • progressive generation of the retina, can lead to blindness, due to deficiency of Vitamin A, retinol
73
Q

Steroid Hormones

A

Corticosteroids and Sex hormones

74
Q

Corticosteroids

A

Aldosterone and cortisol

75
Q

Sex hormones

A

Estrogens, progesterone, and testosterone

76
Q

__________ is the precursor of all classes of steroid hormones.

A

Cholesterol

77
Q

Synthesis and secretion of steroid hormones occur in the:the

A

Adrenal cortex
-cortisol, aldosterone, and androgens

Ovaries/placenta
-estrogen, progestins

Testes
-testosterone

78
Q

How are steroid hormones transferred through tough the body?

A

Blood

79
Q

Steroid hormones are __________, therefore must be complexed with _______ to reach the target organ.

A

Hydrophobic, albumin (plasma protein)